Methods and compositions for administration of oxybutynin

ABSTRACT

Administration of Oxybutynin directly to a patient&#39;s lungs for treating urinary incontinence, respiratory disease or IBD.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of application Ser. No. 12/904,964,filed Oct. 14, 2010, now U.S. Pat. No. 8,415,390 granted Apr. 9, 2013which in turn is a CIP of application Ser. No. 12/130,903, filed May 30,2008, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to a novel method ofadministering Oxybutynin, and to novel forms of Oxybutynin and noveldosage forms containing Oxybutynin adapted for pulmonary route. Theinvention will be described in particular in connection with pulmonarydelivery of Oxybutynin for treatment of respiratory diseases such asasthma and chronic obstructive pulmonary disease (COPD), although otheruses such as prophylactic, therapeutic or ameliorative treatment ofincontinence and intestinal hypermotility, i.e. irritable bowelsyndrome, also are contemplated.

2. Description of the Prior Art

Oxybutynin is a racemic compound of the chemical formula4-diethylaminobut-2-butynyl phenylcyclohexyl-glycolate:

Oxybutynin is an anticholinergic medication that traditionally has beenused to treat urinary incontinence, urge incontinence, frequency andover-active bladder symptoms of incontinence (hereinafter singly andcollectively referred to as “urge urinary incontinence”). Oxybutynin notby decreasing muscle spasms of the bladder. It competitively antagonizesthe M1, M2, and M3 subtypes of the muscarinic acetylcholine receptor. Italso has weaker direct spasmolytic effects on bladder smooth muscle as acalcium antagonist and local anesthetic, but at concentrations far abovethose used clinically. It is available orally in generic formulation andas the chloride salt, and as the brand-names Ditropan® and Ditropan XL®,and as a transdermal patch under the brand-name Oxytrol®.

Oxybutynin currently is administered in oral formulation as a tablet ormultiple tablets and a syrup, or transdermally as a patch or topical gelfor treating urge urinary incontinence. However, oral delivery of atherapeutically active amount of Oxybutynin suffers from a number ofdisadvantages:

-   -   (1) Oxybutynin administered in an oral formulation is absorbed        from the intestinal track at an undesirably slow and uneven rate        with a variable metabolism that leads to undesirable variations        in blood levels and undesirably high dosage rates to achieve a        therapeutic response leading to undesirable side effects;    -   (2) Oxybutynin administered in an oral formulation does not        produce desirably high blood levels in a desirably short period        of time;    -   (3) Oxybutynin administered in an oral formation may result in a        significant amount not reaching targeted tissues because it is        being wasted by metabolism or excretion;    -   (4) Oxybutynin administered in an oral formation is        contraindicated for patients with gastrointestinal obstruction        disorders because of the risk of urinary retention; and    -   (5) Oxybutynin administered in oral formulation requires chronic        dosing with significant and severe side effects, including dry        mouth (xerostomia), constipation, mydriasis, blurred vision,        drowsiness, nausea, palpitations, tachycardia and dizziness.    -   (6) Oxybutynin administered in the oral formulation is subject        to first pass metabolism, resulting in the formation of        metabolite N-desethyloxybutynin (DEO) which has been attributed        to cause the majority of the aforementioned side effects.

As a result, many patients discontinue oral anticholinergic therapy.These adverse effects have been associated with relatively high levelsof Oxybutynin's primary metabolite. DEO, which circulates inconcentrations approximately 4 (Oxybutynin ER) to 10 (Oxybutynin IR)times that of the parent compound. DEO has been shown to have an greateraffinity and binding duration at receptors in the salivary glands thandoes Oxybutynin. In other words, the metabolite DEO has shown to have ahigher side effect-to efficacy ratio than the parent compoundOxybutynin. Levels of DEO in oral and transdermal therapy have beenreported to be approximately 10-40 ng/mL and 3 ng/mL, respectively. Tocompletely eliminate the side effect concerns of this drug, it would beadvantageous to decrease the DEO levels in systemic circulation to belowthose found in current therapies (i.e. below 3 ng/mL).

Moreover, there are other disadvantages to current oral administrationof Oxybutynin, including:

-   -   (7) Oxybutynin administered in an oral formation is administered        as a tablet or multiple tablets which may lack the desirable        ease of administration because some people may dislike the        swallowing of tablets, or may have difficulty swallowing        tablets, or are unable to swallow tablets, or may require a        liquid to assist swallowing of tablets; and    -   (8) Oxybutynin-containing tablets also contain several inactive        ingredients, including significant amounts of lactose, corn        starch, magnesium silicate, magnesium stearate, and talc which        may be considered undesirable because some people may dislike or        be allergic to one or more of these inactive ingredients that        comprise the Oxybutynin tablets.

Transdermal delivery of Oxybutynin has many of the aforesaiddisadvantages. Additionally, some patients suffer skin irritation fromtransdermal patches, have difficulty maintaining and toleratingpatch-to-skin contact, or dislike the aesthetics of a transdermal patch.

Thus, there is a need for improved delivery of Oxybutynin, which willprovide enhanced bioavailability, minimized variations in blood levels,and achieve more rapid onset of activity, as compared to oral dosage ortransdermal dosage forms, while at the same time providing relative easeof administration and reduced side effects compared to current oral andtransdermal delivery methods for administering Oxybutynin.

SUMMARY OF THE INVENTION

The foregoing and other objects of the invention are achieved byproviding methods and compositions for pulmonary delivery of Oxybutyninto a mammalian host, particularly a human patient, whereby to providefor rapid absorption of Oxybutynin while avoiding the above and otherdisadvantages of oral and transdermal administration.

More particularly, it has been discovered that Oxybutynin-containingcompositions can be usefully administered to mammals by pulmonarydelivery at lower dosage levels to elicit a therapeutic response with amarked reduction in systemic metabolites. It is well known to thoseskilled in the art that the major contributor to the untoward effects ofOxybutynin therapy is systemic levels of the metabolite, DEO. Anincreased contribution of DEO toward side effects is due to its greateraffinity toward receptors in non-targeted tissues, i.e. salivary glands.In addition, this invention can provide enhanced bioavailability,achieve more rapid onset of activity, and ease of administration, ascompared to conventional oral and transdermal methods of administration,for treating urinary incontinence. Pulmonary delivery of Oxybutyninprovides relief for treating respiratory diseases such as asthma andchronic obstructive pulmonary disease (COPD), as well as relief fortreating both urinary incontinence and for treating stress urinaryincontinence, as well as intestinal hypermotility, i.e. irritable bowelsyndrome. The present invention also provides novel forms of Oxybutyninas well as novel dosage forms and treatment protocols for administeringOxybutynin.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages of the present invention will be seenfrom the following detailed description, taken in conjunction withaccompanying drawings, in which

FIG. 1 plots inhibition of methacholine induced bronchoconstriction ofOxybutynin and Oxybutynin salts at 18 hours;

FIG. 2 compares inhibition of methacholine induced bronchoconstrictionby Oxybutynin, Oxybutynin salts, tiotropium and glycopyrrolate at 18hours and 24 hours;

FIG. 3 is a series of graphs comparing changes from control responseevoked by methacholine over time by Oxybutynin xinafoate and tiotropiumin pulmonary inflation pressure, mean arterial blood pressure and heartrate; and

FIG. 4 shows pharmacokinetics of pulmonary administration of Oxybutyninover time.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

As used herein, the term “Oxybutynin” is intended to encompass not onlyOxybutynin as an anhydrous powder, but any salt or derivative ofOxybutynin having antispasmodic, anticholinergic activity likeOxybutynin, and which is non-toxic and pharmacologically acceptable, forexample, Oxybutynin hydrochloride or Oxybutynin xinafoate. Othersuitable salts include the palmitate, pamoic, resonate and lauratesalts.

“An effective amount,” as used herein, is an amount of thepharmaceutical composition that is effective for treating urinaryincontinence or irritable bowel syndrome, or pulmonary disease, i.e., anamount of Oxybutynin of a defined aerodynamic particle size suitable forabsorption in the lungs, that is able to reduce or eliminate thesymptoms of urinary and stress incontinence, asthma and COPD.

“A pharmaceutical composition,” as used herein, means a medicament foruse in treating a mammal that comprises Oxybutynin in a dry powder formof a defined aerodynamic particle size prepared in a manner that issuitable for pulmonary administration to a mammal. A pharmaceuticalcomposition according to the invention may also, but does not ofnecessity, include a non-toxic pharmaceutically acceptable carrier.

“A defined aerodynamic particle size,” as used herein, means particleshaving a size sufficiently small so as to be delivered to the lungs. Foroptimal delivery to the lungs, the dry powder form of the Oxybutyninpreferably should be micronized or spray dried to a mass medianaerodynamic diameter powder size of 0.1-10 microns, preferably 0.5-6microns. However, other methods for producing controlled size particles,e.g. supercritical fluid processes, controlled precipitation, etc., alsoadvantageously may be employed.

“A therapeutically effective amount” as used herein will vary with theage, weight and general physical condition of the individual, frequencyof dosing, severity of incontinence, and whether urge or stressincontinence, irritable bowel syndrome, or asthma or COPD is beingtreated. Generally, for treating urge incontinence, a therapeuticallyeffective amount will comprise the active ingredient in a quantity offrom 1 to 20 mg/day, preferably 1 to 10 mg/day. The active ingredientmay be given once a day. Preferably, however, the active ingredient willbe administered in smaller doses two or three or more times a day tomaintain more consistent plasma levels. When used for treating stressincontinence, or irritable bowel syndrome, a therapeutically amount willcomprise the active ingredient in a quantity of from 0.1 to 15 mg perday, preferably 0.2 to 10 mg/day, generally administered as a singledose, or as needed. Generally for treating respiratory diseases, atherapeutically effective amount will comprise the active ingredient ina quantity of from 0.02 to 15 mg/day, preferably 0.05 to 10 mg/day. Theactive ingredient may be given once a day. Preferably, however, theactive ingredient will be administered in smaller doses two or three ormore times a day to maintain more consistent plasma levels.

The Oxybutynin may be delivered in dry powder form, e.g. via a drypowder inhaler (DPI), metered dose inhaler (MDI), or dissolved in asuitable liquid for nebulization in a therapeutically effective unitdose delivery amount. For treating symptoms of stress urinaryincontinence, a dose of Oxybutynin should be taken at the first sign ofstress, or upon onset of the first sign of urgency or just prior toanticipated onset of stress, e.g. just before a patient is scheduled totalk in front of an audience. Similarly, for treating acute symptoms ofrespiratory distress, a dose of Oxybutynin should be taken at the firstsign of respiratory distress. For treatment of chronic respiratorydistress, Oxybutynin should be taken daily according to a regimenrecommended by a physician. In a preferred embodiment of the invention,the dry powder Oxybutynin is packaged for delivery in a piezo-electronicdry powder inhaler such as described in U.S. Pat. No. 6,026,809.

Pulmonary delivery of Oxybutynin to the respiratory tract can be usedadvantageously to treat both urge urinary incontinence and symptoms ofstress urinary incontinence. Unlike conventional oral and transdermaldelivery of Oxybutynin which require chronic dosing with significantside effects and require hours to reach therapeutically active bloodlevels, dry powder pulmonary delivery of Oxybutynin permits a patient toenjoy relief at significantly lower doses with concomitant reduction inside effects such as dry mouth. Dry powder pulmonary delivery ofOxybutynin also permits a patient to enjoy relief from symptoms ofstress urinary incontinence on an as-needed basis. Similarly, dry powderpulmonary delivery of Oxybutynin permits a patient to enjoy prophylacticrelief from symptoms of respiratory distress or on an as needed basis.

A feature and advantage of the present invention that results frompulmonary delivery of Oxybutynin is that the typical primary metaboliteformation of DEO is largely avoided as are the adverse side effectsresulting therefrom as above mentioned.

Additionally, we have found that certain salts of Oxybutynin, whenadministered via pulmonary delivery result in a significantly longeracting efficacy effect than anticipated given that the oral half life isonly 2.5 hours. These salts include not only the chloride salt but alsoa novel salt form of Oxybutynin, namely the xinafoate salt of Oxybutyninwhich heretofore has not been reported in the literature. For example,all dosing of Oxybutynin is typically three times daily due to arelatively short half-life of 2.5 hours with minimal plateau levels ofdrug remaining at approximately eight (8) hours. On the other hand,pulmonary delivery of a salt of Oxybutynin unexpectedly provides aduration of activity in guinea pig lungs of up to 18 hours which wouldtranslate into one to twice daily human dosing. This is illustrated inFIG. 1 attached.

The xinafoate salt of Oxybutynin is prepared by reacting Oxybutynin withxinafoic acid in methyl tert-butyl ether under an inert (nitrogen)atmosphere. Other salts of Oxybutynin that advantageously can beadministered by pulmonary delivery include palmitate, pamoic, resinate,laurate and stearate salts and also esters of Oxybutnin, and provideunexpected results of improved half-life as well as reduced adversemetabolite production.

The following examples are provided to further illustrate the presentinvention:

Example 1

Oxybutynin in crystalline form is micronized to a median aerodynamicparticle size of less than 10 microns. The powder is packaged in a drypowder inhaler (DPI) made in accordance with U.S. Pat. No. 6,026,809.

Example 2

Example 1 was repeated, using micronized Oxybutynin chloride of medianaerodynamic particle size of less than 5 microns in place of Oxybutynin.

Example 3

Example 1 was repeated, using micronized Oxybutynin xinafoate salt ofmaximum aerodynamic particle size of about 10 microns in place ofOxybutynin. The Oxybutynin xinafoate salt was prepared by as follows: A250 mL, round-bottom flask was equipped with a magnetic stirrer, athermocouple, and a nitrogen-inlet adapter. Under nitrogen, the flaskwas charged with Oxybutynin (20.04 g, 0.056 mol.), xinafoic acid (10.69g. 0.057 mol 1.02 equiv, and methyl tert-butyl ether (100 mL, 5 vol).The solids dissolved almost immediately at approximately 18° C. Thebatch was warmed to 50° C., and at approximately 21° C., crystallizationstarted. The mixture was maintained at 50° C. for one hour, was cooledto 33° C. in air, and then in an ice bath to 3° C. The mixture wasmaintained at <5° C. for one hour and was filtered, and the filter cakewas washed with methyl tert-butyl ether (100 mL). The wet cake was driedin a vacuum oven at 45° C. for one hour.

Example 4

Example 1 was repeated, using micronized Oxybutynin base, Oxybutyninhydrochloride salt, and Oxybutynin xinafoate salt of maximum aerodynamicparticle size of about 10 microns in place of Oxybutynin. The level ofbronchodilator activity of Oxybutynin was compared to Tiotropium andGlycopyrrolate 18 and 24 hours after administration in anaesthetizedguinea pigs. FIGS. 1 and 2 shows comparative effects of pulmonarydelivery of Oxybutynin on anaesthetized guinea pigs.

Example 5

Example 1 was repeated, using micronized Oxybutynin xinafoate salt ofmaximum aerodynamic particle size of about 10 microns in place ofOxybutynin. The onset of action and resulting systemic levels ofOxybutynin xinafoate was compared to Tiotropium for the first 6 hoursafter administration in anaesthetized guinea pigs. FIG. 3 compareseffects of pulmonary delivery of Oxybutynin to Tiotropium onanaesthetized guinea pigs in the initial 6 hours after administration.Oxybutynin showed similar protection against methacholine induced airwayconstriction as Tiotropium; however, did not have as significant aninfluence on cardiovascular conditions. FIG. 4 shows the resultingpharmacokinetics of pulmonary administration of Oxybutynin. Systemiclevels of DEO resulting from pulmonary delivery were below the LOQ ofthe detection method and much lower than clinically relevant levels.

Changes may be made without departing from the spirit and scope of theabove-described invention. For example, the Oxybutynin may beco-administered with other compounds or agents for reducing adverse sideeffects or to treat the side effect. For example, cholinergic agonistssuch as described in PCT US09/034018 may be co-administered with theOxybutynin to reduce the effect of dry mouth.

CONCLUSION

Delivery of micronized particles of Oxybutynin directly to the lungs, asneeded, could be found to provide relief to patients suffering fromrespiratory diseases such as asthma and COPD, and also from urge urinaryincontinence and symptoms of stress urinary incontinence and irritablebowel syndrome.

In a guinea pig model of bronchoconstriction, Oxybutynin was found tohave a significantly bronchoprotective effect from 0.25 to 24 hourswithout a prolonged significant effect on arterial pressure and heartrate.

Pulmonary administration of Oxybutynin also avoids significant formationof the first-pass primary metabolite DEO and thus significantly reducesadverse side effects which traditionally have been associated withadministration of Oxybutynin via oral or transdermal delivery.Additionally, dosage amounts of Oxybutynin administered via pulmonarydelivery route are significantly lower than dosage amounts of Oxybutyninwhen delivered via oral or transdermal delivery routes. Furthermore,pulmonary delivery of Oxybutynin results in prolonged therapeutic levelsin the lungs which would permit once or twice daily dosing compared tooral delivery of Oxybutynin which typically is administered three timesdaily.

While the invention has been described in detail herein in accordancewith certain preferred embodiments thereof, many modifications andchanges therein may be affected by those skilled in the art.Accordingly, it is intended that the appended claims cover all suchmodifications and changes as may fall within the spirit and scope of theinvention.

We claim:
 1. A composition comprising oxybutynin xinofoate, and one ormore pharmaceutically acceptable carriers.
 2. The composition of claim1, wherein the oxybutynin xinofoate has a defined aerodynamic particlesize.
 3. The composition of claim 2, wherein the aerodynamic particlesize ranges between 0.1 microns to 10 microns.
 4. The composition ofclaim 3, wherein the aerodynamic particle size ranges between 0.5microns to 8 microns.
 5. The composition of claim 3, wherein theaerodynamic particle size ranges between 0.5 microns to 6 microns. 6.The composition of claim 1, wherein the composition is in dry powderform.
 7. The composition of claim 6, wherein the composition isdelivered via a dry powder inhaler, a metered dose inhaler, or vianebulizer.
 8. The composition of claim 6, wherein the composition isdelivered in a dose of 1 to 20 mg/day.
 9. The composition of claim 6,wherein the composition is delivered in a dose of 1 to 150 mg/day.